Carrier pellets, method for production thereof and use thereof

ABSTRACT

The invention relates to a method for the production of carrier pellets for pharmaceutical active substances. Likewise, the invention relates to such carrier pellets and also to pharmaceutical formulations containing these. The carrier pellets according to the invention are used for transporting and releasing pharmaceutical active substances, in particular in the human body.

The invention relates to a method for the production of carrier pelletsfor pharmaceutical active substances. Likewise, the invention relates tosuch carrier pellets and also to pharmaceutical formulations containingthese. The carrier pellets according to the invention are used fortransporting and releasing pharmaceutical active substances, inparticular in the human body.

Pharmaceutical administration forms which can be applied in particularorally are intended to be formulated suitably for the respectiveapplication in order to effect release of the pharmaceutical activesubstances at the correct time and without disturbing side-effects. Thusactive substances which can be administered for example orally areintended to be released as far as possible such that an unpleasant, e.g.bitter, taste in the mouth is avoided since this can lead to reactionsof repulsion in particular in children. On the other hand, the activesubstances must be released in the stomach or intestine as completely aspossible and in a rapidly absorbable form if a systemic treatment issought.

In the case of oral administration of drugs, the active substance isreleased in the gastro-intestinal tract and a part of the activesubstance is absorbed. By controlling the release of the activesubstance, the degree of absorption and the effective duration can beinfluenced. Correspondingly, various proposals have been made forcontrolling release of the active substance by suitable galenicformulations of the active substance.

One approach resides in providing administration forms with coatings,release of the active substance being able to be influenced as afunction of the solubility or permeability of the coatings. Suchcoatings can be applied for example on tablets or capsules. In thiscase, a disadvantage exists however in that a faulty or damaged coatingcan lead to the fact that the release of the total active substance doseis not controlled in the desired manner.

There are possible, as an alternative, multiparticulate administrationforms in which the total quantity of the active substance is apportionedto a larger number of smaller units, such as pellets. If the individualpellets are provided with coatings, then, in the case of a faultycoating in one pellet, only a correspondingly small proportion of thetotal active substance dose is not subjected to the desired release.

A further advantage of such administration forms based on pelletsresides in the fact that sufficiently small pellets pass into theintestine from the stomach relatively rapidly after ingestion. On theother hand, tablets, as long as they do not disintegrate, can alsoremain in the stomach for a fairly long time, the time in addition beingvery variable.

Known administration forms with controlled release are hence notentirely satisfactory. In addition, the problem exists that desired(prescribed) release profiles generally cannot be set. Furthermore, theproduction of administration forms with controlled release is oftendifficult. Hence there is a requirement for new administration formswith controlled release and also for new methods for the production ofadministration forms with controlled release.

It was therefore the object of the present invention to provide carrierpellets and a method for the production thereof, which enable acontrolled release of the loaded, pharmaceutically effective componentand which do not have the disadvantages of the systems known from thestate of the art.

This object is achieved by the method having the features of claim 1,the carrier pellets having the features of claim 24 and thepharmaceutical formulation having the features of claim 31. The furtherdependent claims reveal advantageous developments. Claim 32 indicates ause according to the invention.

According to the invention, a method for the production of carrierpellets for an active substance is provided in which

-   -   a) a liquid formulation is produced by dissolving and/or        dispersing at least one physiologically well-tolerated pH        regulator in at least one solvent or emulsifier,    -   b) the liquid formulation is introduced by means of nozzles into        a fluidised bed- or spouted bed unit,    -   c) essentially spherical carrier pellets are formed by spray        granulation in the unit in which the solvent is evaporated by        means of a drying gas flow and    -   d) the carrier pellets are discharged continuously from the        unit.

It is preferred that a pH regulator which has a regulating effect in thephysiological surroundings is used, such that the pH value is lowered orincreased and hence the bioavailability of pharmaceutically effectivecomponents is made possible or increased. This can however also beachieved in that the pH regulator has a stabilising function, e.g. whenusing a buffer system as pH regulator.

Preferably, the pH regulator is an organic acid, this being selectedparticularly preferably from the group comprising C₁-C₁₈ mono-, di- andtricarboxylic acids and also mixtures thereof. Representatives of thisgroup, given by way of example, are citric acid, succinic acid, malicacid, fumaric acid, tartaric acid, sorbic acid, adipinic acid, salts andmixtures thereof. It is likewise possible that ascorbic acid or saltsthereof are used as pH regulator.

A further preferred embodiment provides that the at least one pHregulator is an acidic or basic salt.

If the pH regulator is a buffer system, then this preferably comprisesan acidic or basic salt together with a corresponding caustic solutionor acid. Examples of these are citric acid/citrate or tartaricacid/tartrate.

In a further preferred variant, the pH regulator is an organic base,e.g. a purine base or a pyrimidine base, or a mixture of these bases.The purine base is preferably selected from the group comprisingadenine, guanine, hypoxanthine, xanthine and mixtures hereof. Thepyrimidine base is preferably selected from the group comprisingcytosine, uracil, thymine and mixtures hereof.

In the case where the pH regulator is a basic inorganic salt, this ispreferably selected from the group comprising NaHCO₃, K₂CO₃, Na₂CO₃,KHCO₃, Ca(OH)₂, CaO, phosphates and mixtures hereof.

Preferably, the formulation contains in addition at least onephysiologically well-tolerated binder. This binder is thereby preferablyselected from the group comprising methyl celluloses, hydroxymethylcelluloses, hydroxypropylmethyl celluloses, alginates, pectins,polyvinylpyrrolidones, xanthanes and also other hydrocolloids andmixtures hereof.

Preferably water or organic solvents are used as solvents oremulsifiers. As organic solvents, particularly preferred are ethylalcohol, isopropanol, n-propanol or mixtures thereof.

The quantity ratio of pH regulator to binder in the liquid formulationis preferably in the range of 50:50 to 99:1. A preferred liquidformulation has 30 to 80% by weight of the at least one pH regulator,0.5 to 5% by weight of the at least one binder and 15 to 69.5% by weightof the at least one solvent.

The spray granulation can be effected both in a fluidised bed unit andin a spouted bed unit. The temperature in these units is therebypreferably in the range of 5 to 100° C. The drying gas flow entering thecoating unit has, at the entrance into the unit, preferably atemperature in the range of 5 to 120°. There are possible as drying gas,in particular conditioned air, nitrogen or inert gases, e.g. noblegases.

If the spray granulation is effected in a fluidised bed unit, the dryinggas is supplied via a sieve plate. At the same time, the liquidformulation is introduced into the unit by nozzles disposed above thesieve plate.

If the spray granulation is effected in a spouted bed unit, then thedrying gas is supplied through longitudinal gaps situated on the bottom.The liquid formulation is introduced via at least one nozzle disposedbetween the longitudinal gaps.

Preferably, introduction of the liquid formulation is effected throughthe nozzle from below to above.

According to the invention, likewise carrier pellets which contain atleast one physiologically well-tolerated pH regulator are provided.These carrier pellets are produced according to the above-describedmethod.

The carrier pellets preferably have a diameter in the range of 50 μm to1.5 mm, in particular of 90 μm to 1.2 mm.

The carrier pellets are thereby preferably essentially spherical. Thecarrier pellets preferably have a sphericity of 0.8 to 1.0, inparticular of 0.9 to 1.0.

The sphericity is thereby calculated according to the following formula:

${SPHT} = \frac{4\pi \; A}{U^{2}}$

with A=surface area and U=circumference.

The sphericity can be implemented with devices for particle size- andparticle shape analysis with dynamic image analysis. A device suitablefor this purpose is for example the CAMSIZER by Retsch Technology.

Furthermore, it is preferred that the ratio of width to length of thecarrier pellets is in the range of 0.8 to 1.0, in particular of 0.9 to1.0. The ratio of width to length is thereby calculated according to thefollowing formula:

${b/l} = \frac{\min \left( x_{c} \right)}{\min \left( x_{Fe} \right)}$

with x_(Fe)=Feret diameter and x_(c)=maximum width of the particle.

Also the width-length ratio can be determined for example with thementioned CAMSIZER.

Preferably, the carrier pellets according to the invention concern densecarrier pellets, which implies a weight reduction relative to extrusionpellets.

The carrier pellets have essentially the same particle size, i.e. anarrow scatter range with respect to the particle size is present.

The carrier pellets preferably contain at least one physiologicallywell-tolerated binder. This binder is thereby preferably selected fromthe group comprising methyl celluloses, hydroxymethyl celluloses,hydroxypropylmethyl celluloses, alginates, pectins,polyvinylpyrrolidones, xanthanes and also other hydrocolloids and alsomixtures hereof.

According to the invention, likewise a pharmaceutical formulation isprovided, containing the above-described carrier pellets and at leastone active substance.

The carrier pellets according to the invention are used as carrierstructure for pharmaceutically effective components.

EXAMPLE 1 Production of Dicarboxylic Acid Pellets by Means of D/L MalicAcid

1.1 Production of the Spray Solution

The spray solution comprises purified water, methyl cellulose and malicacid. A 4% binder solution is produced from the purified water andmethyl cellulose. This is temperature-controlled at 70° C. Thereafter,the addition of malic acid is effected with constant agitation until acomplete solution is present (proportion of purified water correspondsto proportion of malic acid).

1.2 Particle Formation

The temperature-controlled spray solution is sprayed into the spoutedbed apparatus (ProCell) in the bottom spray method. A constant particleformation is effected by atomising the solids solution in the mainairflow. The latter comprises two partial flows which are producedthrough gap openings, leading along through the process chamber. Theparticle construction takes place by evaporation of the solvent water,malic acid and methyl cellulose remain in the airflow dried asparticles. By means of the defined flow profile of the apparatus, theparticles in the upper process chamber separate from the central airflowand flow laterally, caused by gravity and the suction effect of the mainairflow, back towards the process gas inlet. There, they are entrainedagain with the main airflow and coated continuously with solids from thespray solution. The process air is conditioned.

During the continuous introduction of the solids mixture viaatomisation, the removal of acidic pellets is effected at the same time.The malic acid pellets are fractionated for the desired particle size.

Undersize particles and prepared oversize particles can thereby bereturned to the process. The end product is a homogeneous virtuallyspherical malic acid pellet with a uniform surface structure.

1. A method for the production of carrier pellets for a pharmaceuticallyactive substance, the method comprising: a) producing a liquidformulation by dissolving, dispersing, or a combination of dissolvingand dispersing at least one physiologically well-tolerated pH regulatorin at least one solvent or emulsifier, b) introducing the liquidformulation into a fluidised bed- or spouted bed unit using at least onenozzle, c) forming essentially spherical carrier pellets by spraygranulation in the unit wherein the solvent is evaporated by a dryinggas flow and d) discharging the carrier pellets from the unit.
 2. Themethod according to claim 1, wherein the at least one pH regulator has aregulating effect in physiological surroundings such that the pH valueis lowered or increased and the bioavailability of the pharmaceuticallyactive substance is made possible or increased.
 3. The method accordingto claim 1, wherein the at least one pH regulator comprises at least oneorganic acid selected from the group consisting of ascorbic acid, aC₁-C₁₈ mono-carboxylic acid, a C₁-C₁₈ di-carboxylic acid, a C₁-C₁₈tricarboxylic acid and mixtures thereof.
 4. The method according toclaim 3, wherein the at least one organic acid is selected from thegroup consisting of citric acid, succinic acid, malic acid, fumaricacid, tartaric acid, sorbic acid, adipinic acid, salts thereof, andmixtures thereof.
 5. The method according to claim 1, wherein the atleast one pH regulator comprises an acidic or basic salt.
 6. The methodaccording to claim 1, wherein the pH regulator comprises a buffer systemcomprising an organic acid and salt of the organic acid or an organicbase and salt of the organic base, wherein the buffer system stabilizesthe pH.
 7. The method according to claim 6, wherein the buffer systemcomprises citric acid and a citrate or tartaric acid and a tartrate. 8.The method according to claim 1, wherein the pH regulator acts inphysiological surroundings as pH-increasing, pH-lowering orpH-stabilising.
 9. The method according to claim 1, wherein the pHregulator comprises at least one organic base selected from the groupconsisting of a purine base, a pyrimidine base, and a mixture thereof.10. The method according to claim 9, wherein the purine base is selectedfrom the group consisting of adenine, guanine, hypoxanthine, xanthineand mixtures thereof.
 11. The method according to claim 9, wherein thepyrimidine base is selected from the group consisting of cytosine,uracil, thymine and mixtures thereof.
 12. The method according to claim1, wherein the pH regulator comprises at least one basic inorganic saltselected from the group consisting of NaHCO₃, K₂CO₃, Na₂CO₃, KHCO₃,Ca(OH)₂, CaO, phosphates and mixtures thereof.
 13. The method accordingto claim 1, wherein the liquid formulation further comprises at leastone physiologically well-tolerated binder.
 14. The method according toclaim 13, wherein the at least one binder is selected from the groupconsisting of methyl celluloses, hydroxymethyl celluloses,hydroxypropylmethyl celluloses, alginates, pectins,polyvinylpyrrolidones, xanthanes, hydrocolloids and mixtures thereof.15. The method according to claim 1, wherein the at least one solvent oremulsifier is water or an organic solvent selected from the groupconsisting of ethyl alcohol, isopropanol, n-propanol and mixturesthereof.
 16. The method according to claim 13, wherein the quantityratio of pH regulator to binder in the liquid formulation is in therange of 50:50 to 99:1.
 17. The method according to claim 13, whereinthe liquid formulation contains 30 to 80% by weight of the at least onepH regulator, 0.5 to 5% by weight of the at least one binder and 15 to69.5% by weight of the at least one solvent.
 18. The method according toclaim 1, wherein the temperature in the unit is in the range of 5 to100° C.
 19. The method according to claim 1, wherein the drying gas flowhas, at the entrance into the unit, a temperature in the range of 5 to120°.
 20. The method according to claim 1, wherein the drying gas isair, nitrogen or inert gas.
 21. The method according to claim 1, whereinthe spray granulation is effected in a fluidised bed unit into which thedrying gas is supplied via a sieve plate and the liquid formulation isintroduced by the at least one nozzle disposed above the sieve plate.22. The method according to claim 1, wherein the spray granulation iseffected in a spouted bed unit into which the drying gas is supplied vialongitudinal gaps disposed in the lower half of the unit and the liquidformulation is introduced by the at least one nozzle disposed betweenthe longitudinal gaps.
 23. The method according to claim 22, wherein theintroduction of the liquid formulation is effected through the nozzlefrom below to above.
 24. A carrier pellet for carrying apharmaceutically active substance, the carrier pellet comprising atleast one physiologically well-tolerated pH regulator, wherein thecarrier pellets are produced by the method comprising: a) producing aliquid formulation by dissolving, dispersing, or a combination ofdissolving and dispersing at least one physiologically well-tolerated pHregulator in at least one solvent or emulsifier, b) introducing theliquid formulation into a fluidised bed- or spouted bed unit using atleast one nozzle, c) forming essentially spherical carrier pellets byspray granulation in the unit wherein the solvent is evaporated by adrying gas flow and d) discharging the carrier pellets from the unit.25. The carrier pellet according to claim 24, wherein the carrier pellethas a diameter in the range of 50 μm to 1.5 mm.
 26. The carrier pelletaccording to claim 24, wherein the carrier pellet is essentiallyspherical.
 27. The carrier pellet according to claim 26, wherein thecarrier pellet has a sphericity of 0.8 to 1.0.
 28. The carrier pelletaccording to claim 24, wherein the carrier pellet has a width-lengthratio of 0.8 to 1.0.
 29. The carrier pellet according to claim 24,wherein the carrier pellet is a dense carrier pellet.
 30. A combinationof carrier pellets comprising at least two of the carrier pelletsaccording claim 24, wherein at least two of the carrier pellets in thecombination have essentially the same size.
 31. A pharmaceuticalformulation comprising one or more carrier pellets according to claim 24and at least one pharmaceutically active substance.
 32. A method ofreleasing a pharmaceutically active substance, the method comprising:introducing one or more pharmaceutical formulations according to claim31 into physiological surroundings, wherein the one or more carrierpellets releases the pharmaceutically active substance into thephysiological surroundings.